Abstract
Nutrient availability has profound influence on development. In the nematode C. elegans, nutrient availability governs post-embryonic development. L1-stage larvae remain in a state of developmental arrest after hatching until they feed. This “L1 arrest” (or "L1 diapause") is associated with increased stress resistance, supporting starvation survival. Loss of the transcription factor daf-16/FOXO, an effector of insulin/IGF signaling, results in arrest-defective and starvation-sensitive phenotypes. We show that daf-16/FOXO regulates L1 arrest cell-nonautonomously, suggesting that insulin/IGF signaling regulates at least one additional signaling pathway. We used mRNA-seq to identify candidate signaling molecules affected by daf-16/FOXO during L1 arrest. dbl-1/TGF-β, a ligand for the Sma/Mab pathway, daf-12/NHR and daf-36/oxygenase, an upstream component of the daf-12 steroid hormone signaling pathway, were up-regulated during L1 arrest in a daf-16/FOXO mutant. Using genetic epistasis analysis, we show that dbl-1/TGF-β and daf-12/NHR steroid hormone signaling pathways are required for the daf-16/FOXO arrest-defective phenotype, suggesting that daf-16/FOXO represses dbl-1/TGF-β, daf-12/NHR and daf-36/oxygenase. The dbl-1/TGF-β and daf-12/NHR pathways have not previously been shown to affect L1 development, but we found that disruption of these pathways delayed L1 development in fed larvae, consistent with these pathways promoting development in starved daf-16/FOXO mutants. Though the dbl-1/TGF-β and daf-12/NHR pathways are epistatic to daf-16/FOXO for the arrest-defective phenotype, disruption of these pathways does not suppress starvation sensitivity of daf-16/FOXO mutants. This observation uncouples starvation survival from developmental arrest, indicating that DAF-16/FOXO targets distinct effectors for each phenotype and revealing that inappropriate development during starvation does not cause the early demise of daf-16/FOXO mutants. Overall, this study shows that daf-16/FOXO promotes developmental arrest cell-nonautonomously by repressing pathways that promote larval development.
Highlights
C. elegans L1-stage larvae must feed upon hatching in order to exit developmental arrest
We show that insulin/insulin-like growth factor (IGF) signaling activity in one tissue can affect the development of other tissues, suggesting regulation of additional signaling pathways
We identified two pathways that promote development in fed larvae and are repressed by lack of insulin/IGF signaling in starved larvae
Summary
C. elegans L1-stage larvae must feed upon hatching in order to exit developmental arrest. C. elegans larvae can arrest development during the dauer stage, an alternative to the third larval stage that forms in response to crowding, nutrient stress or high temperature [2]. The insulin/insulin-like growth factor (IGF) signaling pathway is a key regulator of L1 arrest, mediating the systemic response to nutrient availability [3,4]. This study identified the transcription factor PQM-1 as a mediator of daf-16-dependent effects on gene expression. These experiments were done in young adult animals and with a daf-2/InsR mutant background to activate DAF-16/FOXO as opposed to starvation. DAF-16/FOXO target genes that promote L1 arrest are largely unknown. daf-16/ FOXO activates the cyclin-dependent kinase inhibitor cki-1/p27 and represses the developmental timing microRNA lin-4 [3], but whether such regulation is direct is unclear
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